HOMEOSTASIS OF THE ER IN DIFFERENTIATING B CELLS

B 细胞分化过程中 ER 的稳态

• 批准号: 6520338
• 负责人: JOSEPH W BREWER
• 金额: $ 21.28万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520338
• 关键词: B lymphocyte; biological signal transduction; cell differentiation; endoplasmic reticulum; genetically modified animals; laboratory mouse; leukocyte activation /transformation; molecular chaperones

DESCRIPTION (Adapted from the Investigator's abstract): Expression of endoplasmic reticulum (ER) resident molecular chaperones increases when activation B lymphocytes differentiate into high-rate antibody-secreting cells. These chaperones facilitate the proper folding of proteins, including immunoglobulins, in the ER. Therefore, elevated chaperone levels and overall expansion of the ER during B-cell differentiation are likely critical for effective antibody responses. Increased levels of ER chaperones may provide a protective advantage to neoplastic cells, thereby facilitating tumor progression. This coupled with the fact that a variety of disorders including the most common form of cystic fibrosis originate due to aberrant protein folding in the ER underscore the need to understand mechanisms that regulate expression of ER chaperones. The long-term objective of this application is to elucidate the signaling mechanism that controls ER homeostasis in differentiating B-cells. Using the CH12 B-cell line that differentiates in response to defined stimuli, the timing of the induction of ER chaperone expression during B-cell differentiation will be determined. Second, the unfolded protein response (UPR) signaling pathway will be examined in differentiating B-cells. The UPR leads to up-regulated synthesis of ER chaperones when unfolded proteins accumulate in the ER. Third, the role of ER transmembrane signaling proteins (Ern1 and 2) in regulating ER chaperone expression during B-cell differentiation will be investigated. The Ern proteins serve as proximal components of the UPR pathway. Ern mutants will be introduced into B-cells and monitored for their effect on up-regulated synthesis of ER chaperones during differentiation.

描述（改编自研究者摘要）： 内质网（ER）驻留分子伴侣增加时， 活化B淋巴细胞分化为高速率抗体分泌细胞。 这些分子伴侣促进蛋白质的正确折叠，包括 免疫球蛋白，在急诊室。因此，伴侣蛋白水平升高， 在B细胞分化过程中ER的扩增可能是关键的， 有效的抗体反应。ER分子伴侣水平的增加可能提供了一种 对肿瘤细胞的保护优势，从而促进肿瘤 进展再加上一个事实，即各种疾病，包括 囊性纤维化最常见形式起源于异常蛋白 ER中的折叠强调了理解调节 ER伴侣蛋白的表达。本申请的长期目标是 阐明控制ER稳态的信号机制， 分化B细胞使用CH12 B细胞系，该细胞系在 对确定的刺激的反应，ER伴侣蛋白诱导的时间 将测定B细胞分化期间的表达。二是 未折叠蛋白反应（UPR）信号通路将在 分化B细胞UPR导致ER合成上调 当未折叠的蛋白质在ER中积累时，伴侣蛋白起作用。三、ER的作用 跨膜信号蛋白（Ern 1和Ern 2）在调节ER伴侣中的作用 将研究B细胞分化期间的表达。Ern蛋白 作为UPR途径的近端成分。Ern突变体将被引入 并监测它们对ER合成上调的影响 在分化过程中的伴侣。